Therapeutics II: Exam 1 - Drug Induced Diseases RW

What is torsades de pointes (TdP)

Polymorphic ventricular tachycardia

Atypical, rapid and bizzare

Associated with QT prolongation

How is TdP characterized on an EKG?

Characterized by continuously changing axis of polymorphic QRS morphologies

A short, preinitiating RR interval, due to a ventricular couplet

Followed by a long, initiating cycle, due to compensatory pause after the couplet

What QTc interval is considered a concern for TdP?

QTc’s >500 msec are a concern for TdP

What QTc interval is considered prolonged in men?

>450 msec

What QTc interval is considered prolonged in women?

>470 msec

What factors should be considered when assessing risk of TdP?

Patient and drug risk factors

Rarely occurs without multiple risk factors

What conditions predispose patients to TdP?

Age >65

HF

Electrolyte Abnormalities - Hypokalemia or Hypomagnesemia

Female Gender

What drug regimens are a risk factor for TdP?

Drugs that inc. QTc 60 msec from baseline

Drugs that prolong QTc administered IV with a rapid infusion rate

High drug doses/conc.'s (except Quinidine)

Chronic hepatic or renal insufficiency

Combined use of drugs that prolong QT or slow metabolism

Which drug classes are high risk for QT prolongation and TdP?

Cardiac drugs

Antidepressants

Antipsychotics

Antihistamines

Antimicrobials

Which cardiac drugs are associated with QT prolongation?

Amiodarone

Sotalol

Disopyramide

Dofetilide

Procainamide

Quinidine

Which antidepressants are associated with QT prolongation?

SSRIs (citalopram, escitalopram, fluoxetine)

Moclobemide

TCAs

Lithium

Which antipsychotics are associated with QT prolongation?

Amisulpride

Chlorpromazine

Haloperidol

Ziprasidone

Thioridazine

Which antihistamines are associated with QT prolongation?

Loratadine

Astemizole

Diphenhydramine

Which antimicrobials are associated with QT prolongation?

Ciprofloxacin, moxifloxacin, sparfloxacin

Clarithromycin, erythromycin

Fluconazole, voriconazole

Pentamidine

How should risk of TdP be managed in the outpatient setting?

Avoid use of >2 known/possible drugs in pt.'s with hx. of TdP or long QT syndrome

In pt.'s with other risk factors avoid combo of 2 known (or 1 known and 1 possible) QT prolonging drugs

How should risk of TdP be managed in the inpatient setting?

Same as outpatient but also wath electrolytes closely

Consider EKG - if >500 try to avoid all known/possible

What dangerous complications can TdP lead to?

Ventricular fibrillation

Cardiac arrest

Sudden cardiac death

What are non-pharm management options for TdP?

Temporary pacing (atrial or ventricular)

What are pharmacologic management options for TdP?

Magnesium sulfate (1st line)

Isoproterenol

Sodium bicarbonate (for quinidine-mediated arrhythmias)

What are the benefits of magnesium sulfate for treatment of TdP?

Effective for both treatment and prevention of LQT-related ventricular ectopic beats or TdP

Benefit occurs without QT shortening

Benefit occurs in pt.'s with normal serum Mg at baseline

When should sodium bicarbonate be used to treat TdP?

For quinidine-mediated arrhythmias

What is Heparin-Induced Thrombocytopenia (HIT)?

Immune complication of heparin therapy

Paradoxical thrombocytopenia leading to thrombosis

What is the pathophysiology of HIT?

PF-4 binds to surface of platelet

Complexes of heparin and PF-4 form

IgG binds to the PF-4/Heparin complex

IgG/PF-4/Heparin complex activates via the Fc receptor

Fc stimulation leads to generation of pro-coagulant rich microparticles

Why is HIT difficult to correctly diagnose in hospitalized patients?

Hospitalized patients have multiple possible reasons for developing thrombocytopenia

What is the 4T's score used for?

Identify patients at risk for HIT

What are the 4 patient parameters included in the 4T score?

Magnitude of platelet drop

Timing of thrombocytopenia

Presence of new thrombosis

Other possible reasons for thrombocytopenia

Is the 4T score useful for both ruling in and out a diagnosis of HIT?

High negative predictive value - low value rules out HIT

But, high score not always a strong predictor of HIT

What 4T score indicates low risk of HIT?

≤3 is low risk

What 4T score indicates intermediate risk of HIT?

4-5 is intermediate risk

What 4T score indicates high risk of HIT?

≥6 is high risk

What is the typical onset of HIT?

5-10 days after starting heparin

(unless previously exposed)

When does HIT have a rapid onset (<1 day)?

If recently exposed to heparin

Have residual circulating HIT antibodies

What platelet count nadir is seen in most patients with HIT?

<150,000/uL (85%)

(<20,000 seen in 10%)

What is a common complication of HIT?

New thrombosis (in 50%)

What type of venous thrombosis' can occur with HIT, in order from most to least common?

DVT >

PE >

Warfarin-induced limb gangrene >

Adrenal hemorrhagic necrosis >

Cerebral sinus thrombosis

What type of arterial thrombosis' can occur with HIT, in order from most to least common?

Limb artery thrombosis >

Stroke syndrome >

MI >

Mesenteric artery thrombosis

What symptoms can be see in HIT patients due to acute platelet count fall?

Acute inflammatory or cardiorespiratory s/s

What laboratory testing is performed for HIT?

Heparin-dependent platelet activation

Immunoassay (heparin/PF4 antigen)

How is Quinine-/Sulfa-Induced thrombocytopenia differentiated from HIT, in terms of onset?

≥7 days for Quinine-/Sulfa-Induced

(5-10 for HIT)

How is Quinine-/Sulfa-Induced thrombocytopenia differentiated from HIT, in terms of platelet count?

<20,000 uL for Quinine-/Sulfa-Induced

(20,000-150,000 for HIT)

How is Quinine-/Sulfa-Induced thrombocytopenia differentiated from HIT, in terms of complications?

Bleeding seen with Quinine-/Sulfa-Induced

(thrombosis seen with HIT)

How is Quinine-/Sulfa-Induced thrombocytopenia differentiated from HIT, in terms of lab testing?

Drug-dependent increase in platelet-associated IgG for Quinine-/Sulfa-Induced

If HIT is suspected, what should be done first?

Calculate 4T score to determine probability

If a patient has intermediate or high risk of HIT, what should be done?

1. D/C Heparin

2. Start non-heparin anticoagulation

3. Perform ELA

If a patient has intermediate or high risk of HIT, and their ELA returns positive, what should be done?

Obtain functional assay

If positive - continue with management

If negative - resume heparin

If a patient has intermediate or high risk of HIT, and their ELA returns negative, what should be done?

Resume heparin

If a patient has low risk of HIT, what should be done?

Continue heparin

What should always be done before antibody testing in suspected HIT?

4T score

(Ab test has a 20% false positive rate - leads to overdiagnosis)

What is the use of the SRA test in HIT managment?

Will confirm diagnosis

But, takes several days to do

If a patient has a 4T score of 1-4 what should be done?

Continue heparin and monitor platelets

If a patient has a 4T score of 4-5 what should be done?

Stop or change anticoags, and check Ab

If a patient has a 4T score of 7-8 what should be done?

Change to Argatroban/fondaparinux and check HIT Ab

Once a patient has HIT with thrombosis, how long should they be anticoagulated for?

3 months

With Warfarin or DOAC (preferred)

What are alternative anticoagulant options for patients with HIT?

Danaparoid

Argatroban

Bivalirudin

Fondaparinux

What is the interstitium?

Fabric of connective tissue that supports its many structures

Expands and contracts with ventilation

Surrounds the air spaces, brings blood in close proximity to air with separation but minimal impedance to diffusion

Serves as a conduit and fluid channel for lymphatic drainage and the migration of immune cells

Collects and sequesters a fraction of insoluble particles that deposit in the lung

What are the main functions of the interstitium?

Allows for efficient gas exchange

Allows for lymphatic drainage

What are the 2 categories of interstitial disease?

Acute

Chronic

What is acute interstitial disease?

Edema

Infection

Inflammation

(pulmonary edema and exacerbated HF)

What is chronic interstitial disease?

Fibrosis, end stage of inflammation

Often involves bronchiolitis

(inflammation of bronchioles, inc. risk of infection)

What are the operational classifications of interstitial disease?

Pneumoconiosis

Granulomatous disease

Hypersensitivity pneumonitis

Diffuse interstitial fibrosis

What are types of Diffuse interstitial fibrosis?

Idiopathic pulmonary fibrosis (= "usual interstitial pneumonia")

Giant cell interstitial pneumonia ("GIP")

Other interstitial pneumonias

What type of interstitial disease is most commonly caused by drugs?

Hypersensitivity pneumonitis

A type of allergic reaction that causes swelling of Interstitium or parenchyma

If not treated becomes diffuse interstitial fibrosis (commonly idiopathic)

What are methods of diagnosis of interstitial disease?

CT scan

Pulmonary function tests (PFTs)

Biopsy

Look for eosinophils in blood (and in biopsy)

What test is most commonly used for diagnosis of interstitial disease?

Chest film

Why is are eosinophils in blood used for diagnosis of interstitial disease?

Eosinophilia seen commonly with drug induced ILD

Eosinophils are the immune cells primarily responsible for drug allergy

If pt has symptoms and eosinophils in blood - lean towards hypersensitivity pneumonitis

What groups are at a high risk for interstitial disease?

Demographics, family history (some IPF)

Occupational history

Drugs notorious for causing ILD

(Exceptions: sarcoid, IPF)

What is a characteristic of pulmonary function tests in interstitial disease?

Restrictive pattern on PFTs

Reduced FVC, preserved FEV1, decreased RV

Only occurs late in course of disease

What symptoms are seen with interstitial disease?

All non-specific

Dyspnea on exertion

Cough

Fatigue

What are the two types of interstitial disease drugs cause?

Interstitial pneumonia or fibrosis (IPF)

Pulmonary infiltrate with eosinophilia

What drugs cause interstitial pneumonia or fibrosis (IPF)?

Bleomycin (causes both types)

Cocaine

Methotrexate

What drugs cause pulmonary infiltrate with eosinophilia?

Amiodarone

Bleomycin (causes both types)

Nitrofurantoin

What increases the risk of interstitial disease with Nitrofurantoin?

Use for long-term suppressive therapy

What is the onset of Type 1 Amiodarone-induced interstitial disease?

Rapid - 1-3 months after initiation

What are characteristics of Type 1 Amiodarone-induced interstitial disease?

Mild pneumonitis

Resolve on it's own!

What is the onset of Type 2 Amiodarone-induced interstitial disease?

Slow - occurs after years

What are characteristics of Type 2 Amiodarone-induced interstitial disease?

Risk based on total dose given

High mortality rate

Symptoms don't resolve

Periodic CXR considered in pt.'s on long-term amiodarone

How is interstitial disease treated?

Stop offending agent if possible

Steroids - often at high doses for long periods

Steroid sparing agents - little/no data

(Mycophenolate, AZA, NAC)